Systemic thrombolysis with intravenous tissue plasminogen activator (tPA) remains the only proven treatment to improve clinical outcome of patients with acute ischemic stroke. But because of an increased risk of hemorrhage beyond 3 hours post stroke, only certain stroke patients (1-2%) can benefit from tPA. The unfortunate failure of neuroprotective technologies and the current risks and complexity associated with fibrinolytic therapy compels invention of new approaches to reestablish blood flow in stroke victims that are safer and simpler to use. To improve tPA-induced thrombolysis and recanalization rates, we have developed magnetic iron oxide (Fe3O4)-nanomotors, which can perform rotary and forward motion in liquid environment by an external magnetic field. Once the nanomotors encounter the blood clot in the artery, it can either mechanically twirl through the clot to make a larger opening in the clot or act as a beater to wind the blood clot, so that and th cross-linked fibrin mesh (the backbone of a blood clot) can be disrupted. The nanomotors conjugated tPA can target to the ischemic site in vivo under the guidance of an external magnet; therefore, bound tPA can subsequently be efficiently delivered at the site of embolism at high concentration to facilitate thrombolysis. We hypothesize that 1) biodegradable magnetic nanomotors conjugated tPA (nanomotor-tPA) can be delivered to ischemic site under magnetic guidance and 2) blood clots can be mechanically pored and loosened by the nanomotors under a rotating magnetic field, therefore promoting intraclot delivery of both tPA and plasma (substrate for clot lysis) and improving thrombolysis beyond the efficiency currently observed for tPA. To test our hypothesis, the following Specific Aims will be addressed: (1) To characterize the role of nanomotors in thrombolysis in vitro and ex vivo. (2) To characterize the role of nanomotors in thrombolysis in the rat thrombotic model in vivo. If successful, this approach could revolutionize not just the treatment of ischemic stroke but also have majorly impact on other deadly thrombotic diseases such as myocardial infarction and pulmonary embolism.